The present invention relates generally to sulfated oligosaccharides, and in particular to the use of certain sulfated oligosaccharides as agents for lowering blood levels of triglycerides such as, for example in treatment of hypertriglyceridaemia.
It has been proposed that triglycerides may be an independent risk factor for coronary artery disease1-3 and a major study has shown that elevated triglyceride levels, with elevated total cholesterol/HDL cholesterol in coronary patients are associated with an increased risk of further coronary events4. Various forms of hypertriglyceridaernia are associated with varying morbidity5 and one study has shown that plasma triglyceride concentrations have a high predictive power for coronary arterial disease in women6-7.
A number of studies have shown that treatment with heparin, a high molecular weight, N,O-sulfated polysaccharide, affects blood triglyceride levels8,9. Other studies have shown that a heparin derivative, Fragmin, also affects blood triglyceride levels9. Results from various studies with heparin have been inconsistent with regard to effects on triglycerides. Thus, for example, Schrader et al. found that treatment with unfractionated heparin caused a significant increase in triglyceride levels but Fragmin caused no change in triglyceride levels10. Leidig et al. found that acute treatment with heparin invariably caused a decrease in blood levels of triglycerides8. Monreal et al., on the other hand, found that chronic treatment with either heparin or Fragmin caused substantial but not statistically significant increases in blood levels of triglycerides9.
These variable results are probably due to the immense structural diversity of the glycosaminoglycan heparin. It would be anticipated that sulfated oligosaccharides, which are structurally more homogeneous, would more reproducibly and predictably affect blood triglyceride levels.
A number of agents are used to treat hypertriglyceridaemia and its complications including, inter alia, the fibrates, HMG CoA reductase inhibitors and bile acid-binding resins11, although none of these are ideal.
Prior International Patent Application No. PCT/AU96/00238 discloses the preparation of a class of sulfated oligosaccharides based on polymers of monosaccharide units linked by 1xe2x86x922, 1xe2x86x923, 1xe2x86x924 and/or 1xe2x86x926 glycosidic bonds and consisting of from 3 to 8 monosaccharide units, which are potent inhibitors of mammalian heparanases, and can be used to inhibit human angiogenesis, tumour metastasis and inflammation.
In work leading to the present invention, it has been shown that these sulfated oligosaccharides may also be used to lower blood levels of triglycerides.
In accordance with one aspect, the present invention provides a method of lowering blood triglyceride levels in a human or other warm blooded animal which method comprises administering to said animal an effective amount of a sulfated oligosaccharide of Formula (I):
R1xe2x80x94(Rx)nxe2x80x94R2xe2x80x83xe2x80x83(I)
wherein each of R1, R2 and Rx is a monosaccharide unit which may be the same or different and wherein the monosacharide units are linked by 1xe2x86x922, 1xe2x86x923, 1xe2x86x924 and/or 1xe2x86x926 glycosidic bonds; and
n is an integer from 1 to 6.
Preferably, the sulfated oligosaccharides has Formula (II):
Rxxe2x80x94(Rx)nxe2x80x94Rxxe2x80x83xe2x80x83(II)
wherein Rx represents the same monosaccharide unit with adjacent monosaccharide units being linked by 1xe2x86x922, 1xe2x86x923, 1xe2x86x924 and/or 1xe2x86x926 glycosidic bonds, and n is an integer of from 1 to 5 and preferably 3 or 4.
As used herein, terms such as xe2x80x9clowering of blood levels of triglyceridesxe2x80x9d or xe2x80x9clowering of circulating triglyceride levelsxe2x80x9d are intended to encompass both prophylactic and therapeutic treatment of a patient in need of such treatment.